The aim of this project is to create a novel model of human RA that will create a bridge between real patients and scientific research and eventually revolutionize clinical treatment for rheumatoid arthritis (RA). RA is a chronic autoimmune disease, which affects many organs and systems, but mainly attacks synovial joints and leads to cartilage destruction and deformation of the joint, resulting in chronic pain, severe disability an increased mortality. RA affects about 1% of the world's population and about 1.3 million of Americans, mainly during their working-years and has a great social burden. Despite recent progress there are several issues in RA that need to be solved. First, our understanding of the origins of this disease is still far from complete. The roles of individual genetic and environmental factors (such as smoking and air pollution) and their interactions need to be investigated. Also recent findings suggest that RA is not a single uniform disease, but comprises distinct subsets with different causes, clinical course, and response to therapy, namely ACPA+ and ACPA- arthritis. Importantly, the ACPA+ subset correlates with strong genetic susceptibility to RA development. Secondly, there are no predictive screening tests available for RA, which makes early diagnosis (prior to irreversible joint damage) impossible. Finally, up to 20-40% of patients are inadequately controlled on currently available treatments for RA. Having a good animal model of RA would help to find answers to the aforementioned questions. Unfortunately, because of the dramatic differences between human and murine immune systems, currently available animal models will never fully recapitulate human disease. More importantly, these models have no use for discovery of biomarkers or for testing new therapies. Therefore, we will create a new clinically relevant model of human RA in mouse. We will isolate stem cells from cord blood and transplant them into an immunodeficient mouse host, RA-like disease will be induced by immunization with citrullinated collagen or fibrinogen. To study the role of the predisposing genetic factors in development of RA, we will isolate stem cells from cord blood of children being born from mothers with strong genetic predisposition to RA and transplant them to an immunodeficient mouse host. Over time, the transplanted cells will engraft and develop into a fully functional human immune system. Detailed studies of this model will improve our understanding of RA pathogenesis on both molecular and cellular levels. It will also facilitate the search for biomarkers and will be valuable tool for discovery of new therapies, including development of personalized treatments tailored to the needs of specific patients.